Immunomodulation: Cardiovascular Structure and Function

免疫调节：心血管结构和功能

• 批准号: 7111723
• 负责人: DOUGLAS F LARSON
• 金额: $ 36.86万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111723
• 关键词: cardiovascular function; collagen; cytokine; extracellular matrix; fibroblasts; flow cytometry; gene expression; helper T lymphocyte; immunocytochemistry; immunomodulators; laboratory mouse; polymerase chain reaction

DESCRIPTION (provided by applicant): Cardiac extracellular matrix (ECM) and vascular adventitial collagen is composed primarily of fibrillar collagen types I and type III. We propose that CD4+ lymphocytes modulate the cardiovascular fibroblast control of the ECM framework and thus affect the compliance of the ventricular and vascular tissues. The efficacy of neuro-endocrine-based therapeutics in clinical cardiovascular pathological conditions suggests that modulation of fibroblast function affects ECM composition. Similarly, we have shown that supematant from cultured T-lymphocytes markedly changes cardiac flbroblast collagen gene expression in vitro. Moreover, our in vivo data suggest that polarization of CD4+ lymphocytes to Th2 subsets results in increased cardiac diastolic and vascular compliance, whereas Thl polarized lymphocytes results in decreased ventricular and vascular compliance. Therefore we propose that changes in the T-lymphocyte cytokine secretory profile appear to directly alter cardiac and vascular fibroblast gene expression and thereby ECM structure and function. To support our hypothesis, we propose to: 1) define the T-lymphocyte mediators that directly affect cardiac fibroblasts and thus diastolic function; 2) demonstrate that T-lymphocyte secretory factors directly affect the adventitial fibroblast and therefore vascular compliance; and 3) show that adaptive transfer of immunomodulated T-lymphocytes into nai"ve recipient mice changes the cardiac and vascular fibroblast activity and, accordingly, cardiovascular function. These proposed studies will use our established methods to measure gene-structure-function - specifically, lymphocyte and fibroblast gene expression, supported by protein product analysis, and cardiac and vascular function with in vivo quantification of ventricular and vascular mechanics with the Millar Conductance Catheter System. The potential outcome of these studies will be a discovery of a new and novel pathway that will result in innovative therapeutic approaches for the treatment of hypertension, diastolic dysfunction, and heart failure.

描述（由申请人提供）：心脏外基质（ECM）和血管外膜胶原蛋白主要由纤维状胶原型I型和III型组成。 我们建议CD4+淋巴细胞调节ECM框架的心血管成纤维细胞控制，从而影响心室和血管组织的依从性。 基于神经内分泌的疗法在临床心血管病理状况中的功效表明，成纤维细胞功能的调节会影响ECM组成。 同样，我们已经表明，来自培养的T淋巴细胞的超级女性显着改变了体外心脏氟布拉斯特胶原基因表达。 此外，我们的体内数据表明，CD4+淋巴细胞对Th2子集的极化会导致心脏舒张期和血管依从性增加，而THL极化淋巴细胞导致心室和血管依从性降低。 因此，我们建议T-淋巴细胞细胞因子分泌谱的变化似乎直接改变心脏和血管成纤维细胞基因表达，从而直接改变ECM结构和功能。 为了支持我们的假设，我们建议：1）定义直接影响心脏成纤维细胞并因此舒张功能的T淋巴细胞介质； 2）证明T-淋巴细胞分泌因子直接影响外膜成纤维细胞，因此血管依从性； 3）表明，免疫调节的T淋巴细胞的适应性转移到NAI中。“受体小鼠会改变心脏和血管成纤维细胞的活性，因此，这些提出的研究将使用我们既定的研究来使用我们既定的研究来测量我们既定的方法，这些方法是通过 - 特定于基因结构和基因结构进行了分析，淋巴细胞和纤维界的基因表达，源自基因，源自源，源自基因，源自基因，源自基因，卵泡细胞的范围，源自源，源自基因的范围。用Millar电导导管系统对心室和血管力学的体内定量，这些研究的潜在结果将发现一种新的新型途径，这将导致创新的治疗方法，以治疗高血压，舒张功能障碍和心力衰竭。